In the United States each year, more than 350,000 people die from cardiac arrest prior to arriving in the hospital. Even when patients are resuscitated initially, more than half die in the hospital within the first 24 hours. Eisenberg et al., NEJM 306, 1340 (1982). Despite more than three decades of the practice of manual external chest compression or standard cardiopulmonary resuscitation xe2x80x9cstandard CPRxe2x80x9d, together with epinephrine administration, less than 5% of patients who suffer a cardiac arrest survive. Niemann, NEJM, 327, 1075 (1992). Though time to initiation of standard CPR is a critical factor in determining outcome, the inherent limitations of manual external chest compression are perhaps an even greater reason for the poor survival statistics. In light of the tremendous amount of time, money and energy involved in basic CPR performance and training, these statistics become even more disheartening. Although pharmacologic therapy, specifically intravenous epinephrine and antiarrhythmic therapies, have served to improve outcomes in some patients, the role of vasopressor agents during CPR remains controversial. Stiell et al., NEJM, 327, 1045 (1992).
Over the past 35 years since standard manual external chest compression was described, there have been a number of advances in the mechanical means available to improve overall cardiopulmonary resuscitation (xe2x80x9cCPRxe2x80x9d) efficacy. Based on the assumption that increases in intrathoracic pressures will increase cardiac output during ventricular fibrillation, techniques such as the circumferential vest and active compression and decompression (ACD CPR) have been developed. Lurie, Resuscitation, 28, 115 (1994). In an effort to enhance filling of the coronary arteries and enhance venous return during the diastolic or decompression phase of CPR, techniques such as interposed abdominal counterpulsion CPR and use of a rapidly inflating and deflating intra-aortic balloon pump, as well as ACD CPR have been used. Sack et al., JAMA, 267, 379 (1992).
In addition to the research conducted on mechanical means to improve the efficacy of CPR, there has been a renewed interest in developing pharmacological therapies to improve the vital organ blood flow and overall survival of patients who have suffered a cardiac arrest. Such therapies typically include the intravenous administration of epinephrine during the performance of CPR. Epinephrine is an arterial constrictor, and its use is intended to enhance patient blood pressure during the resuscitation process. Even with epinephrine, however, survival after cardiac arrest is poor. Furthermore, recent studies have demonstrated no added benefit from doses of epinephrine higher than the traditional dose. Stiell et al., cited supra. Other recent studies also show no benefit of high or low dose epinephrine with placebo. (Woodhouse et al., Resuscitation, 30, 243 (1995).
U.S. Pat. No. 5,588,422, issued Dec. 31, 1996, discloses a method for resuscitating a patient from cardiac arrest, comprising actively inducing venous blood transport into the heart and arterial blood transport from the heart; ventilating the patient""s lungs; administering to the patient concurrently with said inducing and ventilating steps an arterial constrictor (epinephrine) sufficient to increase the patient""s arterial blood pressure, and an amount of a venodilator (nitroglycerin) sufficient to enhance arterial blood flow to the patient""s brain and heart.
However, a continuing need exists for improved methods and pharmaceutical compositions for use during CPR, which result in enhanced long term survival among at least certain populations of cardiac arrest patients. Such methods and compositions would preferably enhance blood circulation and delivery of oxygenated blood to patient tissue, particularly heart and/or brain tissue, without significantly lessening patient blood pressure.
Surprisingly, it has been found that the administration of L-arginine (which is known to be a substrate for nitric oxide synthase) in combination with the vasopressor epinephrine leads to superior vital organ blood flow during CPR when compared with conventional epinephrine therapy, or with the administration of epinephrine or epinephrine and vasopressin, in combination with nitroglycerin. An increase in both the total myocardial blood flow and the endocardial to epicardial perfusion ratio result. Thus, the present invention provides a method for resuscitating a patient from cardiac arrest, comprising: (a) administering CPR, and (b) administering: i) an amount of one or more vasopressor agents, or one or more vasopressinergic agonists, or a combination thereof, sufficient to increase the patient""s arterial blood pressure; and ii) an amount of L-arginine, nitric oxide, or a direct nitric oxide donor, or a combination thereof, sufficient to enhance arterial blood flow to the patient""s brain and heart.
The invention also provides a kit for the treatment of cardiac arrest comprising packaging material containing: a) an amount of one or more vasopressor agents, or one or more vasopressinergic agonists, or a combination thereof, sufficient to increase a patient""s arterial blood pressure; b) an amount of L-arginine, nitric oxide, or a direct nitric oxide donor, or a combination thereof, sufficient to enhance arterial blood flow to a patient""s brain and heart; and c) instruction means indicating that the compounds described in a) and b) are to be administered to a patient undergoing cardiopulmonary resuscitation.
The invention also provides a pharmaceutical composition comprising: a) an amount of one or more vasopressor agents, or one or more vasopressinergic agonists, or a combination thereof, sufficient to increase arterial blood pressure; b) an amount of L-arginine, nitric oxide, or a nitric oxide donor, or a combination thereof, sufficient to enhance arterial blood flow to the brain and heart; and c) a pharmaceutically acceptable carrier.
The invention also provides the use of a combination of: a) an amount of one or more vasopressor agents, or one or more vasopressinergic agonists, or a combination thereof, sufficient to increase a patient""s arterial blood pressure; and b) an amount of L-arginine, nitric oxide or a direct nitric oxide donor, or a combination thereof, sufficient to enhance arterial blood flow to a patient""s brain and heart; to prepare a medicament useful for enhansing the survival of a cardiac arrest patient.